Cost-effectiveness analysis of abrocitinib compared with standard of care in adult moderate-to-severe atopic dermatitis in Japan.

Atopic dermatitis (AD) is a chronic inflammatory skin disease with a significant clinical, economic, and human burden. The JAK1 Atopic Dermatitis Efficacy and Safety (JADE) program's Phase 3 trials demonstrated that as a treatment for moderate-to-severe AD in adults with previous exposure to immunotherapy, abrocitinib showed superior efficacy and safety compared with standard of care (SoC), consisting of topical corticosteroids. This study assessed the cost-effectiveness of abrocitinib with SoC versus SoC alone for this patient population in Japan from a societal perspective. A hybrid decision tree and Markov model were used to capture the initial treatment and long-term maintenance phases. Clinical inputs at 16 weeks were obtained through a Bayesian network meta-analysis of four pivotal trials from the JADE program. Clinical inputs at 52 weeks were derived from the JADE EXTEND trial. Response-specific utility inputs were obtained from published literature. Resource use, costs, and productivity inputs were gathered from Japanese claims analysis, literature, public documents, and expert opinion. Costs and quality-adjusted life years (QALYs) were discounted at 2.0% per year and incremental cost-effectiveness ratios (ICERs) were calculated. Sensitivity and scenario analyses were performed to validate the base case results and explore a payer perspective. Over a lifetime horizon and with the base-case societal perspective, abrocitinib produced a mean gain of 0.75 QALYs, incremental costs of JPY (¥) 2 270 386 (USD [$] 17 265.6), and a resulting ICER of ¥3 034 514 ($23 076.5) per QALY compared with SoC. From a payer perspective, the incremental costs increased to ¥4 476 777 ($34 044.4), with an ICER of ¥5 983 495 ($45 502.6) per QALY. The results were most sensitive to treatment-specific, response-based utility weights, drug costs, and productivity-related inputs. From a Japanese societal perspective, abrocitinib demonstrated superior QALYs and with a willingness-to-pay threshold of ¥5 000 000 ($38 023.4) per QALY, can be considered cost-effective compared with SoC as a treatment for moderate-to-severe AD in adult patients with previous immunosuppressant exposure.

Degree of Alignment Between Japanese Patients and Physicians on Alopecia Areata Disease Severity and Treatment Satisfaction: A Real-World Survey.

INTRODUCTION: Alopecia areata (AA) is characterized by non-scarring scalp and/or body hair loss and can negatively impact patient mental health. Data are limited on the alignment of patient and physician perceptions of AA severity with each other and with Japanese Dermatological Association (JDA) guideline criteria, and of patient-physician alignment on treatment satisfaction. Therefore, we performed analyses to compare JDA severity groupings with patient-physician alignment on disease severity and to explore treatment satisfaction in AA in Japan. METHODS: Data were drawn from the Adelphi AA Disease Specific Programme (DSP)™, a real-world survey of physicians and patients with AA in Japan conducted January-March 2021. Patients and physicians reported patient AA severity as mild, moderate or severe based on their subjective judgement. Patients were then categorized into five hair loss severity groups according to JDA criteria (S1-5), and patient-physician pairs were matched to assess alignment on severity and treatment satisfaction. RESULTS: Subjective patient- and physician-reported disease severity generally followed JDA severity groupings. The percentage of patient-physician alignment on severity recognition was 76.3% in the overall population. In misaligned pairs, 20.2%, 14.5%, 7.3%, 25.0% and 0.0% of physicians rated disease as more severe than patients in S1, S2, S3, S4 and S5, respectively. Regarding treatment satisfaction, patient-physician alignment was 57.6% in the overall population. In S5, 46.2% of physicians reported being less satisfied than patients. Both physicians and patients cited lack of efficacy as the main reason for dissatisfaction. Of 221 patients, 39.8% and 29.9% were categorized as borderline-abnormal cases for anxiety and depression, respectively. CONCLUSIONS: This study highlights previously unreported patient-physician misalignment on disease severity, level of treatment dissatisfaction and unmet needs due to the lack of effective treatment. Further study on how improvement of the misalignment between physicians and patients could increase both patient and physician satisfaction with treatment and improve the quality of life for patients with AA.

Fli1 deficiency suppresses RALDH1 activity of dermal dendritic cells and related induction of regulatory T cells: a possible role in scleroderma.

BACKGROUND: Aldehyde dehydrogenase 1 family member A1 (RALDH1)-producing dermal dendritic cells (DCs), a conventional DC subset regulating skin fibrosis, are decreased in the involved skin of patients with systemic sclerosis (SSc). In this study, we investigated the contribution of Fli1 deficiency, a potential predisposing factor of SSc, to the phenotypical alteration of RALDH1-producing dermal DCs by using SSc model mice and SSc skin samples. METHODS: Bleomycin (BLM)-induced skin fibrosis was generated with Fli1+/- and wild-type mice. The proportions of DC and CD4+ T cell subsets were determined by flow cytometry in the dermis of BLM-treated mice. Fli1 expression in dermal DCs was evaluated by immunofluorescence with skin samples of SSc and healthy control subjects. RESULTS: RALDH activity of dermal DCs was significantly decreased in BLM-treated Fli1+/- mice compared with BLM-treated wild-type mice, whereas the proportion of CD103-CD11b- dermal DCs, a major DC subset producing RALDH1 in response to BLM injection, was comparable between groups. Relevant to this finding, the proportion of regulatory T cells (Tregs) in the dermis was decreased in BLM-treated Fli1+/- mice relative to BLM-treated wild-type mice, while the proportions of Th1, Th2 and Th17 cells were unaltered. In the involved skin of SSc patients, Fli1 was downregulated in CD11c+ cells, including dermal DCs. CONCLUSIONS: Fli1 deficiency inhibits RALDH1 activity of CD103-CD11b- dermal DCs and related induction of Tregs in BLM-treated mice. Considering Fli1 reduction in SSc dermal DCs, Fli1deficiency may impair the dermal DC-Treg system, contributing to the development of skin fibrosis in SSc.

Serum vasohibin-1 levels: A potential marker of dermal and pulmonary fibrosis in systemic sclerosis.

Vasohibin-1 (VASH-1) is a potent anti-angiogenic factor mainly produced by endothelial cells. In addition, VASH-1 prevents TGF-ß-dependent activation of renal fibroblasts. Since systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy and fibrosis of multiple organs, VASH-1 may be involved in the development of this disease. In this study, we investigated the potential role of VASH-1 in SSc by evaluating the clinical correlation between serum VASH-1 levels and the expression of VASH-1 in SSc-involved skin. Serum VASH-1 levels were higher in SSc patients, especially those with diffuse cutaneous involvement, than in healthy controls and positively correlated with skin score. Furthermore, SSc patients with interstitial lung disease had significantly elevated levels of serum VASH-1 as compared to those without. Importantly, serum VASH-1 levels correlated inversely with both the percentage of predicted vital capacity and the percentage of predicted diffusion lung capacity for carbon monoxide and positively with serum KL-6 levels, but not serum surfactant protein D levels. In SSc-involved skin, VASH1 mRNA was remarkably upregulated compared with healthy control skin, but the major source of VASH-1 was not clear. Fli1 deficiency, a predisposing factor inducing SSc-like endothelial properties, did not affect VASH-1 expression in human dermal microvascular endothelial cells. Collectively, these results suggest that VASH-1 upregulation in the skin and sera is linked to dermal and pulmonary fibrotic changes in SSc, while the contribution of VASH-1 to SSc vasculopathy seems to be limited.

Short chain fatty acids produced by Cutibacterium acnes inhibit biofilm formation by Staphylococcus epidermidis.

Biofilm formation by bacterial pathogens is associated with numerous human diseases and can confer resistance to both antibiotics and host defenses. Many strains of Staphylococcus epidermidis are capable of forming biofilms and are important human pathogens. Since S. epidermidis coexists with abundant Cutibacteria acnes on healthy human skin and does not typically form a biofilm in this environment, we hypothesized that C. acnes may influence biofilm formation of S. epidermidis. Culture supernatants from C. acnes and other species of Cutibacteria inhibited S. epidermidis but did not inhibit biofilms by Pseudomonas aeruginosa or Bacillus subtilis, and inhibited biofilms by S. aureus to a lesser extent. Biofilm inhibitory activity exhibited chemical properties of short chain fatty acids known to be produced from C. acnes. The addition of the pure short chain fatty acids propionic, isobutyric or isovaleric acid to S. epidermidis inhibited biofilm formation and, similarly to C. acnes supernatant, reduced polysaccharide synthesis by S. epidermidis. Both short chain fatty acids and C. acnes culture supernatant also increased sensitivity of S. epidermidis to antibiotic killing under biofilm-forming conditions. These observations suggest the presence of C. acnes in a diverse microbial community with S. epidermidis can be beneficial to the host and demonstrates that short chain fatty acids may be useful to limit formation of a biofilm by S. epidermidis.

Altered Properties of Endothelial Cells and Mesenchymal Stem Cells Underlying the Development of Scleroderma-like Vasculopathy in KLF5+/- ;Fli-1+/- Mice.

OBJECTIVE: In prevous studies, we established a new animal model, KLF5+/- ;Fli-1+/- mice, in which fundamental pathologic features of systemic sclerosis (SSc) are broadly recapitulated. SSc vasculopathy is believed to occur as a result of impaired vascular remodeling, but its detailed mechanism of action remains unknown. To address this, the present study investigated the properties of dermal microvascular endothelial cells (DMECs), bone marrow-derived endothelial progenitor cells (BM-EPCs), and bone marrow-derived mesenchymal stem cells (BM-MSCs), a precursor of pericytes, in KLF5+/- ;Fli-1+/- mice. METHODS: Neovascularization and angiogenesis were assessed in KLF5+/- ;Fli-1+/- mice by in vivo Matrigel plug assay and in vitro tube formation assay, respectively. The properties of mouse BM-EPCs and BM-MSCs were assessed with in vitro studies. Dermal vasculature was visualized in vivo by injecting the mice with fluorescein isothiocyanate-conjugated dextran. RESULTS: Neovascularization was diminished in skin-embedded Matrigel plugs from KLF5+/- ;Fli-1+/- mice. DMECs from KLF5+/- ;Fli-1+/- mice showed defective tubulogenic activity, decreased expression of VE-cadherin and CD31, and an imbalance in the expression of Notch1/Dll4, suggesting that angiogenesis and anastomosis are disturbed. KLF5+/- ;Fli-1+/- mouse BM-MSCs exhibited enhanced proliferation and migration and increased collagen production following stimulation with transforming growth factor ß1, indicating that these cells differentiate preferentially into myofibroblasts rather than pericytes. KLF5+/- ;Fli-1+/- mouse BM-EPCs displayed a transition toward mesenchymal cells, suggesting that vasculogenesis is impaired. Wound healing was delayed in KLF5+/- ;Fli-1+/- mice (mean ± SD healing time 15.67 ± 0.82 days versus 13.50 ± 0.84 days; P = 0.0017), and the vascular network was poorly developed in wound scar tissue. CONCLUSION: The characteristics observed in the KLF5+/- ;Fli-1+/- mouse model - specifically, impaired neovascularization and vascular maturation - are similar to those observed in human SSc, and could be at least partially attributable to the induction of SSc-like properties in DMECs, BM-EPCs, and BM-MSCs. These findings indicate the critical contribution of Klf5 and Fli1 deficiency in vascular cells and related cell precursors to the development of SSc vasculopathy.

Decreased serum cathepsin S levels in patients with systemic sclerosis-associated interstitial lung disease.

Cathepsin S (CTSS) is a lysosomal proteolytic enzyme regulating intracellular and extracellular biological activities, including immunity/inflammation and remodeling of vasculature and extracellular matrix, which are the three cardinal pathological events associated with systemic sclerosis (SSc). To elucidate the potential role of CTSS in the development of SSc, we investigated the clinical correlation of serum CTSS levels. Because serum CTSS levels were inversely correlated with estimated glomerular filtration rate (eGFR) in SSc patients with renal dysfunction (eGFR, <60 min/mL per 1.73 m2 ), SSc patients with normal renal function (eGFR, ≥60 min/mL per 1.73 m2 ) were analyzed. Serum CTSS levels were significantly decreased in diffuse cutaneous SSc patients compared with limited cutaneous SSc patients and healthy controls. Among vascular and fibrotic clinical manifestations, Raynaud's phenomenon and interstitial lung disease (ILD) were relevant to a significant decrease in serum CTSS levels. Importantly, serum CTSS levels negatively correlated with serum levels of Krebs von den Lungen-6 and surfactant protein D in total SSc patients, while not correlating with modified Rodnan total skin thickness score and the percentage of predicted diffusion lung capacity for carbon monoxide and showing a positive trend with the percentage of predicted vital capacity. These results suggest a potential contribution of decreased CTSS expression to the development of ILD in patients with SSc.

Clinical significance of endothelial vasodilatory function evaluated by EndoPAT in patients with systemic sclerosis.

Endothelial dysfunction is a hallmark of vasculopathy associated with systemic sclerosis (SSc). Reactive hyperemia peripheral arterial tonometry is a rapid and non-invasive technique to assess peripheral microvascular endothelial function by measuring changes in digital pulse volume during reactive hyperemia. Low scores of the reactive hyperemia index (RHI) imply an impaired vasodilatory response and, accordingly, impaired endothelial and vascular health. To investigate the clinical significance of the RHI in SSc patients, RHI values were measured in 43 SSc patients and 10 healthy controls. In diffuse cutaneous SSc (dcSSc) patients, RHI values were significantly decreased compared with healthy controls, and inversely correlated with disease duration. In total SSc patients, there was a significant inverse correlation between RHI values and skin score, and interstitial lung disease was associated with the decrease in RHI values. Among vascular symptoms, the current and past history of digital ulcers was seen more frequently in patients with decreased RHI values than in those with normal RHI values. Although no SSc patients had pulmonary arterial hypertension, an inverse correlation was evident between RHI values and mean pulmonary arterial pressure measured by right heart catheterization. These results indicate that the decrease in RHI values is associated with skin fibrosis, interstitial lung disease, digital ulcers and pulmonary vascular involvement leading to pulmonary arterial hypertension, supporting the canonical idea that endothelial dysfunction is a critical event underlying the development of tissue fibrosis and vascular complications in SSc.

Fli1 deficiency induces endothelial adipsin expression, contributing to the onset of pulmonary arterial hypertension in systemic sclerosis.

OBJECTIVES: Adipsin, or complement factor D, is a serine proteinase catalysing complement factor C3 breakdown, leading to the production of opsonin (C3b), membrane attack complex (C5b-C9) and anaphylatoxins (C3a and C5a). Since adipsin is potentially associated with pulmonary arterial hypertension in SSc, we investigated adipsin expression in dermal small vessels of SSc-involved skin, the mechanism regulating adipsin expression in endothelial cells, and the correlation of serum adipsin levels with SSc clinical symptoms. METHODS: Adipsin expression was assessed by immunohistochemistry with skin sections of SSc and healthy subjects. mRNA levels of target genes and transcription factor binding to the ADIPSIN promoter were evaluated by quantitative reverse transcription PCR and chromatin immunoprecipitation, respectively. Serum adipsin levels were determined by enzyme-linked immunosorbent assay. RESULTS: Adipsin expression was remarkably increased in dermal small vessels of SSc-involved skin as compared with those of healthy control skin. Consistent with the notion that Fli1 deficiency induces SSc-like phenotypes in various types of cells, FLI1 siRNA enhanced adipsin expression at protein and mRNA levels and Fli1 bound to the ADIPSIN promoter in human dermal microvascular endothelial cells. Serum adipsin levels were significantly lower in diffuse cutaneous SSc patients than in limited cutaneous SSc patients and healthy controls, and were associated positively with elevated right ventricular systolic pressure and inversely with interstitial lung disease by multivariate regression analysis. CONCLUSION: Adipsin is up-regulated at least partially by Fli1 deficiency in endothelial cells, potentially contributing to the development of pulmonary vascular involvement in SSc.

Solidification of the Lennard-Jones fluid near a wall in thermohydrodynamic lubrication.

We investigate the thermohydrodynamic lubrication of the Lennard-Jones (LJ) fluid in plain wall channels by using a molecular-dynamics simulation. It is found that the LJ fluid solidifies near the wall when the viscous heating of the LJ fluid in the bulk regime is sufficiently large. The thickness of the solidified layer increases with the channel width. Thus, a long-range-ordered crystal-like structure forms near the wall in high-speed lubrication when the channel width is large. The mechanism of this counterintuitive solidification is investigated from both macroscopic and microscopic points of view. It is elucidated that the LJ molecules are densely confined in the vicinity of the wall due to the macroscopic mass and heat transport in the bulk regime. In this densely confined regime, the fluid molecules form a crystal-like structure, which is similar to that of the wall molecules, via direct molecular interaction. Band formation is also observed in the solidified region when the channel width is sufficiently large.

Possible association of decreased serum CXCL14 levels with digital ulcers in patients with systemic sclerosis.

CXCL14 serves as a chemoattractant for activated macrophages, immature dendritic cells and natural killer cells, as well as an antiangiogenic factor by preventing the migration of endothelial cells. CXCL14 also exerts an inhibitory effect on the CXCL12/CXCR4 signaling pathway, which is involved in the maintenance of T-helper (Th)2 bias, and promotes Th1 immune response under the physiological and pathological conditions. Because CXCL14-mediated biological processes seem to be involved in the development of systemic sclerosis (SSc), which is characterized by Th2/Th17-skewed immune polarization and impaired neovascularization, we investigated the clinical correlation of serum CXCL14 levels in patients with this disease. Serum CXCL14 levels were significantly decreased in SSc patients compared with healthy individuals and in diffuse cutaneous SSc patients relative to limited cutaneous SSc patients. SSc patients with digital ulcers had serum CXCL14 levels significantly lower than those without. Furthermore, i.v. cyclophosphamide pulse significantly increased serum CXCL14 levels as compared with the baseline in SSc patients with interstitial lung disease successfully treated with this therapy. These results indicate that decreased CXCL14 expression may contribute to the maintenance of Th2-skewed immune polarization and dysregulated neovascularization, both of which underlie the developmental process of SSc.

A potential contribution of decreased galectin-7 expression in stratified epithelia to the development of cutaneous and oesophageal manifestations in systemic sclerosis.

BACKGROUNDS: Stratified epithelia have caught much attention as potential contributors to the development of dermal and oesophageal fibrosis in systemic sclerosis (SSc). Galectin-7 is a marker of all types of stratified epithelia, which is involved in the maintenance of epidermal homeostasis. So far, the role of galectin-7 has not been studied in SSc. OBJECTIVES: To investigate the potential contribution of galectin-7 to the development of clinical manifestations in SSc. METHODS: Galectin-7 expression was examined in skin samples and cultured keratinocytes by immunostaining and/or quantitative reverse transcription PCR. Serum galectin-7 levels were determined by enzyme-linked immunosorbent assay in 63 SSc and 20 healthy subjects. RESULTS: Galectin-7 expression was markedly decreased in the epidermis of SSc lesional skin compared with that of healthy control skin. Serum galectin-7 levels were significantly lower in SSc patients than in healthy controls and inversely correlated with skin score. In addition, SSc patients with diffuse pigmentation and those with oesophageal dysfunction had significantly decreased serum galectin-7 levels as compared to those without each symptom. Importantly, endothelin-1 stimulation suppressed galectin-7 expression in normal human keratinocytes, and bosentan, a dual endothelin receptor antagonist, reversed circulating galectin-7 levels and epidermal galectin-7 expression in SSc patients. CONCLUSIONS: Galectin-7 downregulation in stratified epithelia, which is mediated at least partially by autocrine endothelin stimulation, may contribute to the development of cutaneous manifestations and oesophageal dysfunction in SSc patients.

Assessment of endothelial function during the loading phase of infliximab in psoriasis: a potential predictor of its drug survival.

BACKGROUND: Tumor necrosis factor inhibitors decrease the risk of cardiovascular events in moderate to severe psoriasis, but the association between their effects on endothelial function and those on skin lesions has not been well studied. We investigated the association between infliximab effects on endothelial function during the loading phase and those on skin lesions in patients with psoriasis. METHODS: We evaluated endothelial function with reactive hyperemia-peripheral arterial tonometry index (RHI) in 15 patients with psoriasis before the first and third infusions of infliximab. Patients were stratified into two groups; those who maintained Psoriasis Area and Severity Index (PASI) 75 response for more than 6 months (defined as responders) and the others (defined as nonresponders). RESULTS: Six weeks after the initiation of infliximab (before the third infusion), PASI scores were significantly improved compared with baseline, while RHI values were not altered in the whole patient group. However, when the responders and the nonresponders were analyzed separately, RHI values tended to be decreased before the third infusion compared with baseline in the nonresponders, while being unchanged in the responders. Importantly, the difference in ∆RHI reached a statistical significance between the two groups, and the cutoff value (mean - 2 standard deviation of RHI values in the responders) identified the nonresponders with 67% of sensitivity and 100% of specificity. CONCLUSIONS: The decrease in RHI values before the third infusion may serve as a predictor for the long-term unfavorable effect of infliximab on psoriatic skin lesions.

Cyclophosphamide Pulse Therapy Normalizes Vascular Abnormalities in a Mouse Model of Systemic Sclerosis Vasculopathy.

Intravenous cyclophosphamide pulse, a standard treatment for systemic sclerosis (SSc)-related interstitial lung disease, elicits a disease-modifying effect on SSc vasculopathy, such as fostering microvascular de-remodeling. To investigate the molecular mechanism by which cyclophosphamide mitigates SSc vasculopathy, we employed endothelial cell-specific Fli1 knockout mice that mimic the functional and structural vascular abnormalities characteristic of SSc. Biweekly cyclophosphamide injection improved vascular permeability and structural abnormalities of endothelial cell-specific Fli1 knockout mice in 2 weeks and in 3 months, respectively. In endothelial cell-specific Fli1 knockout mice, a single dose of cyclophosphamide was sufficient to normalize the decreased expression of α-smooth muscle actin in dermal blood vessels and improve the impaired neovascularization in skin-embedded Matrigel plug. Under the same condition, the decreased expression of vascular endothelial cadherin, platelet-derived growth factor B, S1P1, and CCN1 (molecules associated with angiogenesis and/or vasculogenesis) was reversed along with the reversal of endothelial Fli1 expression. In SSc patients, serum CCN1 levels were significantly increased after intravenous cyclophosphamide pulse. Taken together, these results indicate that cyclophosphamide improves Fli1 deficiency-dependent vascular changes by normalizing the expression of angiogenesis- and vasculogenesis-related molecules and endothelial Fli1, which may help to explain the beneficial effect of cyclophosphamide on SSc vasculopathy.

Increased expression of aquaporin-1 in dermal fibroblasts and dermal microvascular endothelial cells possibly contributes to skin fibrosis and edema in patients with systemic sclerosis.

BACKGROUND: Aquaporin-1 (AQP1), a water channel protein controlling the water contents of cells and tissues, exerts pleiotropic effects on various biological activities, including inflammation, angiogenesis, and extracellular matrix remodeling, by regulating cell behaviors and tissue water balance. OBJECTIVE: To investigate AQP1 roles in systemic sclerosis (SSc) which is characterized by autoimmune inflammation, vasculopathy, and tissue fibrosis. METHODS: AQP1 expression was evaluated by immunohistochemistry and quantitative reverse transcription PCR in skin samples from human and animal models and by immunoblotting in cultured cells. Fli1 binding to the AQP1 promoter was evaluated by chromatin immunoprecipitation. Cell migration was assessed by scratch assay. RESULTS: Dermal fibroblasts and endothelial cells highly expressed AQP1 in SSc lesional skin, and AQP1 expression in dermal fibroblasts and endothelial cells positively correlated with the degrees of tissue fibrosis and edema, respectively. Consistently, SSc dermal fibroblasts up-regulated AQP1 compared with normal dermal fibroblasts in vitro. Furthermore, TGF-ß stimulation induced AQP1 expression in normal dermal fibroblasts, while TGF-ß1 antisense oligonucleotide suppressed AQP1 expression in SSc dermal fibroblasts. In endothelial cells, Fli1 deficiency resulted in AQP1 up-regulation in vivo and in vitro and Fli1 bound to the AQP1 promoter. Importantly, SSc dermal fibroblasts and FLI1 siRNA-treated endothelial cells had a pro-migratory property, which was remarkably diminished by gene silencing of AQP1. CONCLUSION: AQP1 is up-regulated in SSc dermal fibroblasts and SSc endothelial cells at least partially due to autocrine TGF-ß stimulation and Fli1 deficiency, respectively, possibly contributing to inflammation, vasculopathy, and tissue fibrosis by regulating tissue edema and cell migration.

Progranulin overproduction due to constitutively activated c-Abl/PKC-δ/Fli1 pathway contributes to the resistance of dermal fibroblasts to the anti-fibrotic effect of tumor necrosis factor-α in localized scleroderma.

BACKGROUND: Dermal fibroblasts derived from patients with systemic sclerosis (SSc) overproduce progranulin (PGRN), an endogenous antagonist of tumor necrosis factor (TNF) receptors, due to the deficiency of transcription factor Fli1. Fli1 expression is also decreased in dermal fibroblasts derived from patients with localized scleroderma (LSc). OBJECTIVE: To investigate the expression levels of PGRN and its contribution to the induction of pro-fibrotic phenotype in LSc dermal fibroblasts. METHODS: PGRN expression levels were determined by immunohistochemistry and quantitative reverse transcription PCR in the skin of human subjects. The role of PGRN in fibroblast activation was examined with gene silencing technique. The involvement of c-Abl/protein kinase C (PKC)-δ/Fli1 pathway in the regulation of PGRN expression was investigated by immunoblotting. RESULTS: The expression levels of PGRN and TNF-α were elevated in LSc skin lesions compared with healthy control skin. LSc dermal fibroblasts were less responsive to the anti-fibrotic effect of TNF-α than normal dermal fibroblasts. Importantly, gene silencing of PGRN reversed the response to TNF-α in LSc dermal fibroblasts. Similar to SSc dermal fibroblasts, the inhibition of c-Abl/PKC-δ/Fli1 pathway by gene silencing of ABL1 or PRKCD significantly suppressed PGRN expression in LSc dermal fibroblasts. CONCLUSION: PGRN overproduction due to constitutively activated c-Abl/PKC-δ/Fli1 pathway may contribute to the resistance of LSc dermal fibroblasts to the anti-fibrotic effect of TNF-α, which may be involved in maintaining their pro-fibrotic phenotype under the pro-inflammatory condition, as is the case with SSc.